2-pyridinyl-6,7,8,9-tetrahydropyrimido[1,2-a] pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo[1,2-a] pyrimidin-5(1H)one derivatives

ABSTRACT

The invention relates to therapeutic uses of a pyrimidone derivative represented by formula (I) or a salt thereof: 
     
       
         
         
             
             
         
       
     
     Wherein X, Y, R1, R2, m and n are as defined herein. Specifically, a medicament comprising the said derivative or a salt thereof as an active ingredient is used for preventive and/or therapeutic treatment of a neurodegenerative diseases caused by abnormal activity of GSK3β such as Alzheimer&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/227,007, filed Sep. 15, 2005, now abandoned, which is a continuationof U.S. application Ser. No. 10/362,850, filed Jun. 17, 2003, now U.S.Pat. No. 6,974,819, Issued Dec. 13, 2005, which was the National Stageof International application No. PCT/EP01/10,726, filed Aug. 31, 2001,all of which are incorporated herein by reference in their entirety;which claims the benefit of priority of European Patent Application No.00/402410.5, filed Sep. 1, 2000 and European Patent Application No.00/402412.1, filed Sep. 1, 2000.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral tauopathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitinilation dependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation. Although tau hyperphosphorylation results in adestabilization of the neuronal cytoskeleton, the pathologicalconsequences of abnormal GSK3β activity are, most likely, not only dueto a pathological phosphorylation of tau protein because, as mentionedabove, an excessive activity of this kinase may affect survival throughthe modulation of the expression of apoptotic and antiapoptotic factors.Moreover, it has been shown that β-amyloid-induced increase in GSK3βactivity results in the phosphorylation and, hence the inhibition ofpyruvate dehydrogenase, a pivotal enzyme in energy production andacetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseases.These include, in a non-limiting manner, Parkinson's disease,tauopathies (e.g. frontotemporoparietal dementia, corticobasaldegeneration, Pick's disease, progressive supranuclear palsy) and otherdementia including vascular dementia; acute stroke and others traumaticinjuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; peripheral neuropathies;retinopathies and glaucoma. In addition GSK3β may find application inthe treatment of other diseases such as: Non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; cancers such as breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides pyrimidone derivatives representedby formula (I) or salts thereof, solvates thereof or hydrates thereof:

wherein:X represents hydrogen atoms, a sulfur atom, an oxygen atom or a C₁₋₂alkyl group and a hydrogen atom;Y represents a bond, an ethenylene group, an ethynylene group, a1,2-cyclopropylene, an oxygen atom, a sulfur atom, a sulfonyl group, asulfinyl group, a carbonyl group, a nitrogen atom being optionallysubstituted by a C₁₋₆ alkyl group, a phenyl or a benzyl group; or amethylene group optionally substituted by one or two groups chosen froma C₁₋₆ alkyl group, a phenyl group, a hydroxyl group or a C₁₋₄ alkoxygroup;R1 represents a 2, 3 or 4-pyridyl group optionally substituted by a C₃₋₆cycloalkyl group a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a benzyl groupor a halogen atom;

when Y represents a bond, a 1,2-cyclopropylene, a methylene groupoptionally substituted or a carbonyl group then R2 represents a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₄ alkylthio group, a C₁₋₄alkoxy group, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a 5,6,7,8-tetrahydronaphthyl ring, a naphthyl ring, aphenylthio group, a benzyl group, a phenyl ring, a pyridyl ring, anindole ring, a pyrrole ring, a thiophene ring, a furan ring or animidazole ring; the benzyl group or the rings being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, amethylenedioxy group, a halogen atom, a C₁₋₂ perhalogenated alkyl group,a C₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, anitro, a cyano, an amino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀dialkylamino group, a C₁₋₆ alkylcarbonylamino group, a C_(6,10)arylcarbonylamino group, a C₁₋₄ alkylsulfonyl group, C₁₋₄alkylsulfonyloxy group or a phenyl group;

when Y represents an ethenylene group, an ethynylene group, an oxygenatom, a sulfur atom, a sulfonyl group, a sulfinyl group or a nitrogenatom being optionally substituted then R2 represents a C₁₋₆ alkyl group,a C₃₋₆ cycloalkyl group, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃halogenated alkyl group, a naphthyl ring, a 5,6,7,8-tetrahydronaphthylring, a benzyl group, a phenyl ring, a pyridyl ring, an indole ring, apyrrole ring, a thiophene ring, a furan ring or an imidazole ring; thebenzyl group or the rings being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a methylenedioxy group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, anamino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀ dialkylamino group, a C₁₋₆alkylcarbonylamino group, a C_(6,10) arylcarbonylamino group, a C₁₋₄alkylsulfonyl group, C₁₋₄ alkylsulfonyloxy group or a phenyl group;

m represents 1 or 2;

and n represents 0 to 3.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;manic depressive illness; schizophrenia; alopecia; cancers such asbreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia and several virus-induced tumors.

As further preferred embodiments of the present invention, there areprovided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, tauopathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma, and the aforementioned medicament in the form ofpharmaceutical composition containing the above substance as an activeingredient together with one or more pharmaceutical additives.

The present invention further provides an inhibitor of GSK3β activitycomprising as an active ingredient a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and the saltsthereof, and the solvates thereof and the hydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof; and a use of a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedalkyl group having 1 to 6 carbon atoms, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexylgroup, and the like;

The C₃₋₆ cycloalkyl group represents a cyclic alkyl group having from 3to 6 carbon atoms;

The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The C₁₋₄ alkylthio group represents an alkylthio group having 1 to 4carbon atoms for example, methylthio group, ethylthio group, propylthiogroup, isopropylthio group, butylthio group, isobutylthio group,sec-butylthio group, tert-butylthio group, and the like;

The C₁₋₄ alkylsulfonyl group represents an alkylsulfonyl group having 1to 4 carbon atoms for example, methylsulfonyl group, ethylsulfonylgroup, propylsulfonyl group, isopropylsulfonyl group, butylsulfonylgroup, isobutylsulfonyl group, sec-butylsulfonyl group,tert-butylsulfonyl group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen have been substituted by halogen atoms, for example aCF₃ or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has not been substituted by a halogen atom;

The C₁₋₅ monoalkylamino group represents an amino group substituted byone C₁₋₅ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group and isopentylaminogroup;

The C₂₋₁₀ dialkylamino group represents an amino group substituted bytwo C₁₋₅ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group;

The C₁₋₆ alkylcarbonylamino group represents an amino group substitutedby a C₁₋₆ acyl group, for example, formyl group, acetyl group, propionylgroup, pivaloyl group, butyryl group, isobutyryl group, pentanoyl group,3-methylbutyryl group and hexanoyl group;

The C_(6,10) arylcarbonylamino group represents an amino groupsubstituted by a benzoyl group and a naphthoyl group;

The ethenylene, ethynylene and the 1,2-cyclopropylene group representsrespectively the following groups:

The leaving group represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid.

The acid-addition salts of the basic compounds are prepared by standardprocedures well know in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the pyrimidinone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention. Thepyrimidinone derivatives represented by the aforementioned formula (I)may have one or more asymmetric carbon atoms. As for the stereochemistryof such asymmetric carbon atoms, they may independently be in either (R)and (S) configuration, and the pyrimidinone derivative may exist asstereoisomers such as optical isomers, or diastereoisomers. Anystereoisomers in pure form, any mixtures of stereoisomers, racemates andthe like fall within the scope of the present invention.

Examples of preferred compounds of the present invention are shown intable 1 hereinafter. However, the scope of the present invention is notlimited by these compounds.

Preferred compounds of the present invention represented by formula (I)include also:

-   (1) Compounds wherein R1 represents a 3- or 4-pyridyl group and more    preferably 4-pyridyl group, which may be substituted by a C₁₋₂ alkyl    group, C₁₋₂ alkoxy group or a halogen atom; and/or-   (2) Compounds wherein X represents hydrogen atoms, an oxygen atom or    a methyl group and a hydrogen atom; and/or-   (3) Compounds wherein Y represents a bond, an ethenylene group, an    ethynylene group, an oxygen atom, a sulfur atom, a sulfinyl group, a    carbonyl group, a methylene group optionally substituted or a    nitrogen atom being optionally substituted by one or two benzyl    group; and/or-   (4) R2 represents a C₁₋₄ alkyl group, C₁₋₂ alkylthio group, C₁₋₂    alkoxy group, a trifluoromethyl group, a C₅₋₆ cycloalkyl group, a    naphthyl ring, a 5,6,7,8-tetrahydronaphthyl ring, a phenylthio    group, a benzyl group, a phenyl ring, a pyridyl ring, an indole    ring, a thiophene ring; the rings being optionally substituted by 1    to 4 substituents.    More preferred compounds of the present invention represented by    formula (I) include also:-   (1) Compounds wherein R1 represents an unsubstituted 4-pyridyl    group; and/or-   (2) Compounds wherein R2 represents a C₁₋₄ alkyl group, C₁₋₂    alkylthio group, C₁₋₂ alkoxy group, a trifluoromethyl group, a C₅₋₆    cycloalkyl group, a naphthyl ring, a 5,6,7,8-tetrahydronaphthyl    ring, a phenyl ring, a pyridyl ring, an indole ring, a thiophene    ring; the rings being optionally substituted by 1 to 4 substituents;    and/or-   (3) Compounds wherein X represents hydrogen atoms, an oxygen atom or    a methyl group and a hydrogen atom; and/or-   (4) Compounds wherein Y represents a bond, a ethenylene, a    ethynylene, a sulfur atom, an oxygen atom, a carbonyl group, a    sulfinyl group, a methylene group optionally substituted by a C₁₋₄    alkyl group and/or a hydroxy group, or a nitrogen atom optionally    substituted by one or two benzyl group; and/or-   (5) n is 0, 1 or 2.    Particularly preferred compounds of the present invention    represented by formula (I) include the compounds of table 1:-   1:    9-[2-(H-indol-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   2:    9-(3-phenylpropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   3:    9-(2-phenylethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   4:    9-[3-(1H-indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   5:    9-(2-phenoxyethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   6:    9-[3-(3,4-methylenedioxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   7:    9-[2-(2-methoxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   8:    9-[2-(4-fluorophenoxyethyl)]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   9:    9-[3-(2-chlorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   10:    9-[3-(4-methylpheny)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   11:    9-[3-(4-trifluoromethylphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   12:    9-(4-phenylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   13:    9-[3-(2-methylphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   14:    9-[2-(2,5-dimethoxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   15:    9-[2-(2-methoxyphenoxy)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   16:    9-[3-(2-methoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   17:    9-[2-(4-chlorophenoxy)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   18:    9-[3-(3-methoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   19:    9-(2-methoxyphenylmethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   20:    9-[2-phenylthioethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   21:    9-[3-(3,4-dimethoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   22:    9-[3-(3,4,5-trimethoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   23:    9-[2-(phenylsulfonyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   24:    9-[3-(3,4-fluorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   25:    9-[3-phenylpropanoyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   26:    9-[3-(4-fluorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   27:    9-[3-(2,5-dimethoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   28:    9-[3-(2,4-dichlorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   29:    9-[3-(3-fluorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   30:    9-[3-(4-chlorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   31:    9-(3,3-dimethylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   32:    9-(2-cyclohexylethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   33:    9-[3-(pyridin-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   34:    9-[2-(4-methylsulfonyloxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   35:    9-(3-methylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   36:    9-(3,3-diphenylpropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   37:    9-[4-(4-methoxyphenyl)butyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   38:    9-[4-(4-nitrophenyl)butyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   39:    9-[3-(2-fluorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   40:    9-(3-phenylprop-2-ynyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   41:    9-(3-phenylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   42:    9-[2-(2-chloro-4-fluorophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   43:    9-(2-phenyl-2-oxo-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   44:    9-(3-benzyloxypropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   45:    9-(3-methylthioethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   46:    9-[2-(1-naphthyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   47:    9-[2-(thiophen-2-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   48:    9-[2-(3-trifluoromethylphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   49:    9-[(2-(thiophen-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   50:    9-[2-(2-bromophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   51:    9-(4-cyclohexylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   52:    9-[2-(3-bromophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   53:    9-[2-(4-tert-butylphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   54:    9-[2-(2,4,6-trimethylphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   55:    9-[2-(4-ethoxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   56:    9-[2-(2-chloro-6-fluorophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   57:    9-[2-(3-chlorophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   58:    9-[2-(3-methylphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   59:    9-(3-methoxybutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   60:    9-(3-cyclohexylpropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   61:    9-[3-[di(phenylmethyl)amino]propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   62:    9-(2-phenyl-cyclopropylmethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   63:    9-(3-phenylprop-2-enyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   64:    9-(2-phenyl-2-hydroxypropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   65:    9-[3-(4-fluorophenyl)-3-oxo-propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   66:    9-(4,4,4-trifluorobutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   67:    9-[3-phenyl-3-oxo-propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   68:    9-[3-phenyl-3-hydroxypropyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   69:    9-[3,3,3-trifluoro-2-hydroxypropyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   70:    (R)-9-[2-phenyl-2-hydroxyethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   71:    (S)-9-[2-phenyl-2-hydroxyethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   72:    9-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   73:    9-[1-methyl-2-oxo-2-phenyl-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   74:    9-[1-methyl-2-hydroxy-2-phenyl-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   75:    9-[2-(4-methylphenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   76:    9-[2-(4-chlorophenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   77:    9-[2-(4-fluorophenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   78:    9-[2-(4-phenylphenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   79:    9-[2-(3-methoxyphenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   80:    9-[2-(2-naphthyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   81:    9-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   82:    9-[2-(3-methoxy-4,5-methylendioxyphenyl)-2-oxo-1-methylethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   83:    9-[2-(4-methylphenyl)-2-hydroxy-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   84:    9-[2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-hydroxy-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   85:    9-[2-(phenylamino)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   86:    9-[2-(3-chlorophenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   87:    9-[2-(3-chlorophenyl)-2-hydroxy-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   88:    9-[2-(3-fluorophenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   89:    9-[2-(3-fluorophenyl)-2-hydroxy-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;    And the compounds of table 2:-   1:    1-[2-(1H-Indol-3-yl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H-one,-   2:    1-[3-(phenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   3:    1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   4:    1-[2-(phenyl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   5:    1-[3-(2-methylphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   6:    1-[3-(2-methoxyphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   7:    1-(4-phenylbutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   8:    1-[3-(2-chlorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   9:    1-[3-(2,5-dimethoxyphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   10    :1-[3-(4-methylphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   11:    1-[3-(3-methoxyphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   12:    1-[3-(3,4,5-trimethoxyphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   13:    1-[2-(4-fluorophenoxy)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   14:    1-[2-(4-chlorophenoxy)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   15:    1-[3-(2,4-dichlorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   16:    1-[2-(phenylthio)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1-one,-   17:    1-(3-phenylpropanoyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H-one,-   18:    1-[3-(4-fluorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   19:    1-[3-(3,4-difluorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   20:    1-(2-cyclohexylethyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   21:    1-(3,3-dimethylbutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one.-   22:    1-(2-phenyl-2-oxo-ethyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,    and-   23:    (S)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one.-   24:    1-(4,4,4-trifluoro-but-2-en-1-yl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   25:    1-[3-(4-trifluoromethylphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   26:    (R)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   27:    1-[3-(2-fluorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   28:    1-[2-(2,5-dimethoxy-phenyl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   29:    1-[2-(phenylsulfonyl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   30:    1-(4,4,4-trifluorobutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1-one,-   31:    1-[3-(pyridin-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H-one,-   32:    1-[2-(2-methoxy)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   33:    1-[2-(4-chloro-phenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   34:    1-[2-(naphth-2-yl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   35:    1-[2-(3-methoxy-4,5-methylendioxy-phenyl)-2-oxo-1-methyl-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   36:    1-[2-(4-phenyl-phenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   37:    1-[2-(4-methylphenyl)2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   38:    1-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   39:    1-[2-(4-fluorophenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,-   40:    1-[2-(3-methoxyphenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one.    As a further object, the present invention concerns also methods for    preparing the pyrimidin-4-one compounds represented by the    aforementioned formula (I). These compounds can be prepared, for    example, according to methods explained below.    Preparation Method

2-[1,2-a]pyrimidin-4-one compounds represented by the aforementionedformula (I) may be prepared according to scheme 1.

(In the above scheme the definition of R1, R2, X, Y and n are the sameas those already described for compound of formula (I)).

The [1,2-a]pyrimidin-4-one derivative represented by the above formula(III), wherein R1 is as defined for compound of formula (I), is allowedto react with a base such as sodium hydride, sodium carbonate orpotassium carbonate, in a solvent such as N,N-dimethylformamide,N-methylpyrrolidine, N,N-dimethylacetamide or chloroform, at a suitabletemperature ranging from 0 to 130° C. under ordinary air, and then witha compound of formula (II), wherein R2, Y and n are as defined forcompound of formula (I) and L represents a leaving group, to obtain thecompound of the aforementioned formula (I).

Preferably when X represents hydrogen atoms, L represents a bromide ormesyl group and the reaction is carried out with sodium hydride inN,N-dimethylformamide at a suitable temperature ranging from 70 to 130°C.

Preferably when X represents oxygen atom, L represents a chloride andthe reaction is carried out with sodium hydride in chloroform at asuitable temperature ranging from 0 to 70° C.

Compound of formula (II) is commercially available or may be synthesizedaccording to well-known methods of one skilled in the art.

The compound of formula (III) may be prepared according to the methoddefined in scheme 2.

(In the above scheme the definition of R1 is the same as alreadydescribed.) According to this method, the 3-ketoester of formula (IV) isallowed to react with a compound 2 of formula (V). The reaction may becarried out in an alcoholic solvent such as ethanol, propanol orisopropanol, in presence of a base such as sodium hydride, sodiumcarbonate or potassium carbonate, at a suitable temperature ranging from25°-100° C. under ordinary air.

Compound of formula (IV) is commercially available or may be synthesizedaccording to well-known methods of one skilled in the art.

For example compounds of formula (IV), wherein R1 represent a pyridylgroup optionally substituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group ora halogen atom, can be prepared by reacting a nicotinic acid optionallysubstituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or an halogen, witha malonic acid monoester. The reaction can be carried out using methodswell known to one skilled in the art, such as for example in presence ofa coupling agent such as 1,1′-carbonylbis-1H-imidazole in a solvent suchas tetrahydrofuran at a temperature ranging from 20 to 70° C.

Compound of formula (V) may be synthesized according to the methoddescribed by Smith and Christensen (J. Org. Chem. 1955, 20, 829).

Alternatively and when Y represents an oxygen atom, X representshydrogen atoms and R2 represents an aryl or heteroaryl group, compoundsof the aforementioned formula (I) may be prepared according to scheme 3.

(In the above scheme the definition of R1 is the same as alreadydescribed.)

According to this method, compounds of formula (III), are allowed toreact with a base such as sodium hydride or potassium carbonate in asolvent such as N,N-dimethylformamide at a suitable temperature rangingfrom 70° to 130° C. under ordinary air, then followed by additioncompounds of formula (VI), wherein Pg represents a protecting group,preferably a tetrahydropyran, and L represents a leaving group,preferably a bromide. The deprotection is then carried out using methodswell known to one skilled in the art, such as for example when theprotecting group is a tetrahydropyran group, the deprotection is thencarried out in presence of ammonium chloride in a solvent such asmethanol at a temperature ranging from 20° to 70° C. to give compound offormula (VII). Compounds of formula (I), as defined hereinabove, canthen be prepared by reacting the compound of formula (VII) with acompound of formula (VIII) using methods well known to one skilled inthe art, such as for example in presence of triphenylphosphine anddiethylazodicarboxylate as coupling agent in a solvent suchtetrahydrofuran at room temperature.

Compounds of formula (VI) and (VIII) are commercially available or maybe synthesized according to well-known methods of one skilled in theart.

In the above reactions, protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of a functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, tauopathies(e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; cancers such as breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES

The present invention will be explained more specifically with referenceto the following general examples, however, the scope of the presentinvention is not limited to these examples.

Example 1 Compound N^(o) 7 of Table 19-[2-(2-Methoxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one(Z)-but-2-enedioate (1:1) 1.1.2-Pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 8.98 g (46.5 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionateand 8.0 g (46.5 mmol) of 2-amino tetrahydropyrimidine dihydrochloride(prepared according to J. Org. Chem. 1955, 20, 829.) and 19.3 g (139.5mmol) of potassium carbonate in 60 ml of ethanol was heated at refluxtemperature during 18 h.

The cooled solution was evaporated to remove solvent and the residue wastreated with water and extracted with dichloromethane. The extracts weredried and evaporated to give 8.0 g (75%) of product as a white powder.Mp: 219° C.

1.2.9-[2-(2-Methoxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one(Z)-but-2-enedioate (1:1)

A suspension of 0.25 g (1.09 mmol) of2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 3ml of anhydrous dimethylformamide was treated with 57 mg (1.42 mmol) ofsodium hydride (60% suspension in mineral oil) and the resulting mixturewas heated at 70° C. for 30 min. 0.327 g (1.42 mmol) of1-[2-(methylsulfonyloxy)ethyl]-2-methoxybenzene (prepared according toJ. Med. Chem. 1983, 26(1), 42) was added and the reaction mixture washeated at 130° C. during 1 h. The cooled solution was treated with waterand extracted with ethyl acetate. The organic phase was dried andevaporated to give crude product, which was purified by silica gelchromatography, eluting with dichloromethane/methanol in the proportions100/0 to 95/5. The 0.338 g of pure product obtained in the form of freebase was dissolved in hot ethanol and treated with 1 equivalent of(Z)-but-2-enedioïc acid. The cooled solution was filtered to afford0.325 g (62%) of white solid. Mp: 157-160° C.

Example 2 Compound N^(o) 4 of Table 19-[3-(1H-Indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one2.1. 3-(1H-Indol-3-yl)propanol (J. Med. Chem. (1995), 38(11), 1998)

To a suspension of 4.8 g (126.8 mmol) of lithium aluminum hydride in 240ml of diethylether at 0° C. was added dropwise 10 g (52.8 mmol) of3-(1H-indol-3-yl)propanoic acid dissolved in 430 ml of diethylether andthe resulting mixture stirred at room temperature for 1 h.

The reaction mixture was diluted with 100 ml of diethylether at 0° C.and treated with excess of a saturated aqueous solution of sodiumsulfate. Further solid sodium sulfate was added and the organic phasewas filtered to remove salts. The solvent was evaporated to dryness togive 9 g (98%) of product as an oil.

2.2. 3-(1H-Indol-3-yl)propyl bromide (Chem. Pharm. Bull. (1988), 36(8),2853)

To a solution of 2 g (11.41 mmol) of 3-(1H-indol-3-yl)propanol in 40 mlof dioxane was added at room temperature 5.3 g (12.55 mmol) ofdibromotriphenylphosphorane and the resulting solution was stirredduring 18 h.

An excess of cyclohexane was added and the resulting precipitate wasfiltered and discarded. The solvent was evaporated to dryness to give2.7 g (99%) of product as an oil which was used in the subsequent stepwithout further purification.

2.3.9-[3-(1H-Indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.30 g (1.31 mmol) of2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 8ml of anhydrous dimethylformamide was treated with 68 mg (1.44 mmol) ofsodium hydride (60% suspension in mineral oil) and the resulting mixturewas heated at 70° C. for 30 min. 0.407 g (1.71 mmol) of3-(1H-indol-3-yl)propyl bromide was added and the reaction mixture washeated at 130° C. during 18 h.

The cooled solution was treated with water and extracted with ethylacetate. The organic phase was dried and evaporated to give crudeproduct which was purified by silica gel chromatography, eluting withdichloromethane/methanol/ammonia in the proportions 98/2/0.2 to 90/10/1to afford 0.3 g (59%) of pure product.

Mp: 230-232° C.

Example 3 Compound N^(o) 15 of Table 19-(2-(2-Methoxyphenoxyethyl))-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one(Z)-but-2-enedioate (1:1) 3.1.9-(2-Hydroxyethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.30 g (1.31 mmol) of2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 6ml of anhydrous dimethylformamide was treated with 63 mg (1.58 mmol) ofsodium hydride (60% suspension in mineral oil) and the resulting mixturewas heated at 70° C. for 30 min. 0.329 g (1.58 mmol) of2-(2-bromoethoxy)tetrahydro-2H-pyran was added and the reaction mixturewas heated at 130° C. during 1 h.

The cooled solution was treated with water and extracted with ethylacetate. The organic phase was dried and evaporated to give an oil,which was dissolved in 2 ml of methanol and treated with 0.127 g ofammonium chloride. The resulting mixture was heated for 18 h at refluxtemperature.

The cooled solution was evaporated to dryness and the residue treatedwith water and solid potassium carbonate and extracted withdichloromethane. The organic phase was evaporated to give 0.158 g (49%)of product as an oil which was used without further purification.

3.2.9-(2-(2-Methoxyphenoxyethyl))-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one(Z)-but-2-enedioate (1:1)

To a solution of 0.146 g (0.536 mmol) of9-(2-hydroxyethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 4 ml of tetrahydrofuran under argon atmosphere, was added 0.197 g(0.75 mmol) of triphenylphosphine, 0.080 g (0.643 mmol) 2-methoxyphenoland 0.131 g (0.75 mmol) of diethylazodicarboxylate. The reaction mixturewas stirred for 1 h.

The solvent was evaporated and the residue was treated with water anddilute aqueous hydrochloric acid and washed with diethylether. Theaqueous phase was neutralized with solid potassium carbonate andextracted with dichloromethane. Evaporation of the organic phase gavecrude product, which was purified by chromatography on silica gel,eluting with dichloromethane/methanol/ammonia in the proportions95/5/0.5 to give 0.080 g of product in the form of a free base.Treatment with 1 equivalent of (Z)-but-2-enedioïc acid in ethanolafforded 0.060 g (23%) of product.

Mp: 140-142° C.

Example 4 Compound N^(o) 25 of Table 19-[3-Phenylpropanoyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.2 g (0.87 mmol) of2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 5ml of chloroform was treated with 26 mg (1.14 mmol) of sodium hydride(60% suspension in mineral oil) and the resulting mixture was stirred atroom temperature for 15 min and then cooled to 0° C. 0.148 g (0.964mmol) of 3-phenylpropionyl chloride was added and the reaction mixturewas stirred at room temperature during 18 h.

The reaction mixture was washed with a saturated aqueous solution ofammonium chloride and dried and evaporated. The residue was purified bychromatography on silica gel eluting with dichloromethane/methanol inthe proportion 100/0 to 95/5 to afford give 0.120 mg (38%) of pureproduct as a white solid.

Mp: 137-140° C.

A list of chemical structures and physical data for compounds of theaforementioned formula (I) illustrating the present invention is givenin table 1 and 2. The compounds have been prepared according to themethods of the example.

Example 5 Compound N^(o) 3 of Table 21-[3-(1H-Indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one5.1. 7-Pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one

A mixture containing 8 g (41.4 mmol) of ethyl3-(4-pyridyl)-3-oxopropionate and 14 g (164 mmol) of4,5-dihydro-1H-imidazol-2-ylamine in 75 ml of ethanol was heated atreflux temperature during 18 h.

The solvent was evaporated and the crude product was purified bychromatography on silica gel eluting with a mixture ofdichloromethane/methanol in the proportions 100/0 to 90/10 to obtain 6.3g of 7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one as freebase.

Mp: 318-320° C.

5.2. 3-(1H-Indol-3-yl)propanol (J. Med. Chem. (1995), 38(11), 1998)

To a suspension of 4.8 g (126.8 mmol) of lithium aluminum hydride in 240ml of diethylether at 0° C. was added dropwise 10 g (52.8 mmol) of3-(1H-indol-3-yl)propanoic acid dissolved in 430 ml of diethylether andthe resulting mixture stirred at room temperature for 1 h.

The reaction mixture was diluted with 100 ml of diethylether at 0° C.and treated with excess of a saturated aqueous solution of sodiumsulfate. Further solid sodium sulfate was added and the organic phasewas filtered to remove salts. The solvent was evaporated to dryness togive 9 g (98%) of product as an oil.

5.3. 3-(1H-Indol-3-yl)propyl bromide (Chem. Pharm. Bull. (1988), 36(8),2853)

To a solution of 2 g (11.41 mmol) of 3-(1H-indol-3-yl)propanol in 40 mlof dioxane was added at room temperature 5.3 g (12.55 mmol) ofdibromotriphenylphosphorane and the resulting solution was stirredduring 18 h.

An excess of cyclohexane was added and the resulting precipitate wasfiltered and discarded. The solvent was evaporated to dryness to give2.7 g (99%) of product as an oil which was used in the subsequent stepwithout further purification.

5.4.1-[3-(1H-Indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one

To a suspension of 0.19 g (0.89 mmol) of7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 10 ml ofanhydrous N,N-dimethylformamide was added 0.135 g (0.97 mmol) ofpotassium carbonate and the resulting mixture was heated at 130° C.during 10 min. There is added 0.232 g (0.97 mmol) of3-(1H-indol-3-yl)propyl bromide and heating is continued for 3 h.

The cooled suspension is treated with water, extracted with ethylacetate and the organic extracts dried over sodium sulfate. The crudeproduct was purified by chromatography on silica gel eluting with amixture dichloromethane/methanol/ammonia in the ratio 90/10/1 to afford0.18 g of pure product.

Mp: 218-220° C.

Example 6 Compound N^(o) 16 of Table 21-[2-(Phenylthio)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-onehydrochloride (1:1)

To a suspension of 0.2 g (0.93 mmol) of7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in ml ofanhydrous N,N-dimethylformamide was added 48.5 mg (1.21 mmol) of sodiumhydride (60% suspension in mineral oil) and the resulting mixture washeated at 70° C. during 30 min. There was added 0.32 g (1.49 mmol) of2-bromoethyl phenyl sulfide and heating was continued at 130° C. during1 h. Water was added to the cooled mixture and the resulting solutionextracted with ethyl acetate. The combined extracts were washed withwater and evaporated. The crude product was purified by chromatographyon silica gel eluting with a mixture ofdichloromethane/methanol/diethylamine in the proportions 98/2/0.2 toobtain pure compound as free base. The compound was converted to thehydrochloride salt by addition of hydrochloric acid to an isopropylicsolution of the free base. There is obtained 0.11 g of product as ayellow solid.

Mp: 199-202° C.

Example 7 Compound N^(o) 14 of Table 21-[2-(4-Chlorophenoxy)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H-onehydrochloride (1:1)

To a suspension of 0.2 g (0.93 mmol) of7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 5 ml ofanhydrous N,N-dimethylformamide was added 48.5 mg (1.21 mmol) of sodiumhydride (60% suspension in mineral oil) and the resulting mixture washeated at 70° C. for 30 min. 0.351 g (1.49 mmol) of2-(4-chlorophenoxy)ethyl bromide was added and the reaction mixture washeated at 130° C. during 18 h.

Water was added to the cooled mixture and the resulting solutionextracted with ethyl acetate. The combined extracts were washed withwater and evaporated. The crude product was purified by chromatographyon silica gel eluting with a mixture of dichloromethane/methanol in theproportions 100/0 to 96/4 to obtain pure compound as free base. Thecompound was converted to the hydrochloride salt by addition ofhydrochloric acid to an ethanolic solution of the free base. There isobtained 0.24 g of product as a yellow solid.

Mp: 211-213° C.

Example 8 Compound N^(o) 17 of Table 21-[-(3-Phenyl)propanoyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one

A suspension of 0.2 g (0.93 mmol) of7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 5 ml ofN,N-dimethylformamide was treated with 48 mg (1.20 mmol) of sodiumhydride (60% suspension in mineral oil) and the resulting mixture wasstirred at room temperature for 15 min and then cooled to 0° C. 0.251 g(1.49 mmol) of 3-phenylpropionyl chloride was added and the reactionmixture was stirred at room temperature during 18 h.

The reaction mixture was washed with a saturated aqueous solution ofammonium chloride and dried and evaporated. The residue was purified bychromatography on silica gel eluting with dichloromethane/methanol inthe proportion 100/0 to 95/5 to afford give 0.2 g of pure product as awhite solid.

Mp: 171-172° C.

In the table, R1 is an unsubstituted 4-pyridyl group, Ph represents aphenyl group, in the column “X”, when X represents two hydrogen atoms,only “H” is indicated, and in the column R2, “______” indicates the bondattached to the Y group.

TABLE 1 (I)

N^(o) X Y R2 n Mp ° C. salt  1 H CH₂

0 217-219 (1:1) (+/−) 2,3-dihydroxy butanedioate  2 H CH₂ Ph 1 130-132(1:1) (Z)-but-2-enedioate  3 H CH₂ Ph 0 141-143 (1:1)(Z)-but-2-enedioate  4 H CH₂

1 230-232 base  5 H O Ph 1 190-192 (1:1) (Z)-but-2-enedioate  6 H CH₂

1 150-152 (1:1) (Z)-but-2-enedioate  7 H CH₂

0 157-160 (1:1) (Z)-but-2-enedioate  8 H O

1 161-163 (1:1) (Z)-but-2-enedioate  9 H CH₂

1 128-130 (1:1) (Z)-but-2-enedioate 10 H CH₂

1 157-159 (1:1) (Z)-but-2-enedioate 11 H CH₂

1 160-162 (1:1) (Z)-but-2-enedioate 12 H CH₂ Ph 2 156-158 (1:1)(Z)-but-2-enedioate 13 H CH₂

1 160-162 (1:1) (Z)-but-2-enedioate 14 H CH₂

0 160-162 (1:1) (Z)-but-2-enedioate 15 H O

1 140-142 (1:1) (Z)-but-2-enedioate 16 H CH₂

1 153-155 (1:1) (Z)-but-2-enedioate 17 H O

1 223-225 (1:1) hydrochloride 18 H CH₂

1 238-240 (1:1) hydrochloride 19 H bond

0 258-260 (1:1) hydrochloride 20 H S Ph 1 215-217 (1:1) hydrochloride 21H CH₂

1 176-178 (1:1) hydrochloride 22 H CH₂

1 225-227 (1:1) hydrochloride 23 H SO₂ Ph 1 254-256 (1:1) hydrochloride24 H CH₂

1 215-217 (1:1) hydrochloride 25 O CH₂ Ph 1 137-140 base 26 H CH₂

1 245-247 (1:1) hydrochloride 27 H CH₂

1 245-247 (1:1) hydrochloride 28 H CH₂

1 208-210 (1:1) hydrochloride 29 H CH₂

1 221-223 (1:1) hydrochloride 30 H CH₂

1 222-224 (1:1) hydrochloride 31 H CH₂

0 166-167 base 32 H CH₂

0 134-135 base 33 H CH₂

1  81.5 base 34 H CH₂

0 148.8 base 35 H CH₂

0 137.4 base 36 H PhCH Ph 1 154.3 base 37 H CH₂

2  89.3 base 38 H CH₂

2 140.4 base 39 H CH₂

1 243-245 (1:1) hydrochloride 40 H ≡ Ph 0 235-237 (1:1) hydrochloride 41H CHCH₃ Ph 1 222-224 (1:1) hydrochloride 42 H CH₂

0 268-272 (1:1) hydrochloride 43 H CO Ph 0 284-286 (1:1) hydrochoride[M + H]⁺ N^(o) X Y R2 n Observed salt 44 H O

2 391 base 45 H CH₂ SMe 2 331 base 46 H CH₂

0 383 base 47 H CH₂

0 339 base 48 H CH₂

0 401 base 49 H CH₂

0 339 base 50 H CH₂

0 412 base 51 H CH₂

2 367 base 52 H CH₂

0 412 base 53 H CH₂

0 389 base 54 H CH₂

0 375 base 55 H CH₂

0 377 base 56 H CH₂

0 385 base 57 H CH₂

0 367 base 58 H CH₂

0 347 base 59 H CHCH₃ OCH₃ 1 315 base 60 H CH₂

1 353 base 61 H

2 466 Base 62 H

Ph 0 213-216 Hydrochloride 63 H

Ph 0 264-266 Hydrochloride 64 H C(OH)(CH₃) Ph 0 126-129 (Z)-but-racemate enedioate 65 H CO

1 226-229 hydrochloride 66 H CH₂

1 254-256 hydrochloride 67 H CO Ph 1 136-138 (Z)-but- enedioate 68 HCH(OH) Ph 1 147-149 base racemate 69 H CH(OH) racemate

0 248-250 hydrochloride 70 H CH(OH) Ph 0 232-234 hydrochloride (+)-(R)71 H CH(OH) Ph 0 220-222 hydrochloride (−)-(S) 72 H CH(OH) racemate

1 145-147 base  73* H, CH₃ CO Ph 0 194-196 hydrochloride (rac)  74* H,CH₃ CH(OH) Ph 0 232-234 base (rac) racemate 75 H CO

0 263-264 hydrochloride 76 H CO

0 247 hydrochloride 77 H CO

0 245 hydrochloride 78 H CO

0 140-141 hydrochloride 79 H CO

0 204-205 hydrochloride 80 H CO

0 217-218 hydrochloride 81 H CO

0 209-210 Hydrochloride  82* H, CH₃ (rac) CO

0 233-234 hydrochloride 83 H CH(OH) racemate

0 157-158 base 84 H CH(OH) racemate

0 248-249 Base 85 H CO

0 220-222 Base 86 H CO

0 263-265 hydrochloride 87 H CH(OH) racemate

0 172-174 base 88 H CO

0 273-275 hydrochloride 89 H CH(OH) racemate

0 96-98 base

TABLE 2

N^(o) R1 Y X R2 n Mp ° C. salt 1 4-py CH₂ H

0 205-207 (Z)-but-enedioate 2 4-py CH₂ H Ph 1 258-260 (Z)-but-enedioate3 4-py CH₂ H

1 218-220 base 4 4-py CH₂ H Ph 0 158-160 (Z)-but-enedioate 5 4-py CH₂ H

1 224-225 hydrochloride 6 4-py CH₂ H

1 228-229 hydrochloride 7 4-py CH₂ H Ph 2 238.5-240   hydrochloride 84-py CH₂ H

1 222-223 hydrochloride 9 4-py CH₂ H

1 208-209 hydrochloride 10 4-py CH₂ H

1 227-228 hydrochloride 11 4-py CH₂ H

1 190-191 hydrochloride 12 4-py CH₂ H

1 197-201 hydrochloride 13 4-py O H

1 205-207 hydrochloride 14 4-py O H

1 211-213 Hydrochloride 15 4-py CH₂ H

1 207-208 hydrochloride 16 4-py S H Ph 1 199-202 hydrochloride 17 4-pyCH₂ O Ph 1 170 base 18 4-py CH₂ H

1 251-252 hydrochloride 19 4-py CH₂ H

1 187-188 hydrochloride 20 4-py CH₂ H

0 117-118 base 21 4-py CH₂ H

0 142-143 base 22 4-py CO H Ph 0 252-256 hydrochloride 23 4-py CH(OH) HCF₃ 1 191-192 base (S) 24 4-py ═ H CF₃ 0 136-138 base (trans) 25 4-pyCH₂ H

1 136-137 base 26 4-py CH(OH) H CF3 1 187-189 base (R) 27 4-py CH₂ H

1 201-203 hydrochloride 28 4-py CH₂ H

0 221-223 hydrochloride 29 4-py SO₂ H Ph 1 261-264 base 30 4-py CH₂ HCF₃ 1 261-263 hydrochloride 31 4-py CH₂ H

1 186-187 hydrochloride 32 4-py CH₂ H

0 240-242 hydrochloride 33 4-py CO H

0 241-242 hydrochloride 34 4-py CO H

0 284-285 hydrochloride 35 4-py CO CH₃ (Rac)

0 252-253 hydrochloride 36 4-py CO H

0 238-239 hydrochloride 37 4-py CO H

0 226-227 hydrochloride 38 4-py CO H

0 233-234 Hydrochloride 39 4-py CO H

0 250-251 Hydrochloride 40 4-py CO H

0 238-239 hydrochloride

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Two different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta. Inhibitors were solubilized in DMSO (final solventconcentration in the reaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated 33P radioactivity was determinedby liquid scintillation spectrometry. The phosphorylated GS-1 peptidehad the following sequence: NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 is between 2 nanomolar to 1 micromolarconcentrations.

Formulation Example (1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1 30 mg Crystalline cellulose 60 mg Corn starch 100mg Lactose 200 mg Magnesium stearate 4 mg

(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20 mg(1) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of neurodegenerative diseases caused byabnormal activity of GSK3β.

1. A method of inhibiting the activity of glycogen synthase kinase3-beta (GSK3-β), which comprises administering to a patient in need ofsaid inhibition a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof:

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, anethenylene group, an ethynylene group, a 1,2-cyclopropylene, an oxygenatom, a sulfur atom, a sulfonyl group, a sulfinyl group, a carbonylgroup, an NH group being optionally substituted by a C₁₋₆ alkyl group, aphenyl or a benzyl group; or a methylene group optionally substituted byone or two groups chosen from a C₁₋₆ alkyl group, a phenyl group, ahydroxyl group and a C₁₋₄ alkoxy group; R1 represents a 2, 3 or4-pyridyl group optionally substituted by a C₃₋₆ cycloalkyl group, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a benzyl group or a halogen atom;when Y represents a bond, a 1,2-cyclopropylene, a methylene groupoptionally substituted or a carbonyl group then R2 represents a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₄ alkylthio group, a C₁₋₄alkoxy group, a perhalogenated alkyl group, a C₁₋₃ halogenated alkylgroup, a 5,6,7,8-tetrahydronaphthyl ring, a naphthyl ring, a phenylthiogroup, a benzyl group, a phenyl ring, a pyridyl ring, an indole ring, apyrrole ring, a thiophene ring, a furan ring or an imidazole ring; thebenzyl group or the rings being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a methylenedioxy group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, anamino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀ dialkyl-amino group, a C₁₋₆alkylcarbonylamino group, a C_(6,10) arylcarbonylamino group, a C₁₋₄alkyl-sulfonyl group, C₁₋₄ alkylsulfonyloxy group and a phenyl group;when Y represents an ethenylene group, an ethynylene group, an oxygenatom, a sulfur atom, a sulfonyl group, a sulfinyl group or an NH groupbeing optionally substituted then R2 represents a C₁₋₆ alkyl group, aC₃₋₆ cycloalkyl group, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃halogenated alkyl group, a naphthyl ring, a 5,6,7,8-tetrahydronaphthylring, a benzyl group, a phenyl ring, a pyridyl ring, an indole ring, apyrrole ring, a thiophene ring, a furan ring or an imidazole ring; thebenzyl group or the rings being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a methylenedioxy group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, anamino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀ dialkylamino group, a C₁₋₆alkylcarbonylamino group, a C_(6,10) arylcarbonylamino group, a C₁₋₄alkylsulfonyl group, a C₁₋₄ alkylsulfonyloxy group and a phenyl group; mrepresents 1 or 2; and n represents 0 to
 3. 2. The method according toclaim 1, wherein in said compound of formula I, R1 represents anunsubstituted 4-pyridyl group.
 3. The method according to claim 2,wherein in said compound according to formula I, R2 represents a C₁₋₄alkyl group, C₁₋₂ alkylthio group, C₁₋₂ alkoxy group, a trifluoromethylgroup, a C₅₋₆ cycloalkyl group, a naphthyl ring, a5,6,7,8-tetrahydronaphthyl ring, a phenyl ring, a pyridyl ring, anindole ring, a thiophene ring; the rings being optionally substituted by1 to 4 substituents.
 4. The method according to claim 1, wherein saidcompound of formula I is selected from the group consisting of:9-[2-(1H-indol-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-phenylpropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-phenylethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(1H-indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-phenoxyethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(3,4-methylenedioxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-methoxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-fluorophenoxyethyl)]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(2-chlorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(4-methylphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(4-trifluoromethylphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(4-phenylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(2-methylphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2,5-dimethoxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-methoxyphenoxy)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(2-methoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-chlorophenoxy)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(3-methoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-methoxyphenylmethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-phenylthioethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(3,4-dimethoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(3,4,5-trimethoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(phenylsulfonyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(3,4-fluorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-phenylpropanoyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(4-fluorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(2,5-dimethoxyphenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(2,4-dichlorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(3-fluorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(4-chlorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3,3-dimethylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-cyclohexylethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(pyridin-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-methylsulfonyloxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-methylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3,3-diphenylpropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[4-(4-methoxyphenyl)butyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[4-(4-nitrophenyl)butyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(2-fluorophenyl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-phenylprop-2-ynyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-phenylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-chloro-4-fluorophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-phenyl-2-oxo-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-benzyloxypropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-methylthiobutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(1-naphthyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(thiophen-2-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-trifluoromethylphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[(2-(thiophen-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-bromophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(4-cyclohexylbutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-ter-butylphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2,4,6-trimethylphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-ethoxyphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-chloro-6-fluorophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-chlorophenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-methylphenyl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-methoxybutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-cyclohexylpropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-[di(phenylmethyl)amino]propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-phenyl-cyclopropylmethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(3-phenylprop-2-enyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-phenyl-2-hydroxypropyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(4-fluorophenyl)-3-oxo-propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(4,4,4-trifluorobutyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-phenyl-3-oxo-propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-phenyl-3-hydroxypropyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3,3,3-trifluoro-2-hydroxypropyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;(R)-9-[2-phenyl-2-hydroxyethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;(S)-9-[2-phenyl-2-hydroxyethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[1-methyl-2-oxo-2-phenyl-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[1-methyl-2-hydroxy-2-phenyl-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-methylphenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-chlorophenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-fluorophenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-phenylphenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-methoxyphenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-naphthyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapht-2-yl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-methoxy-4,5-methylendioxyphenyl)-2-oxo-1-methylethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-methylphenyl)-2-hydroxy-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(1,1,4,4,-tetramethyl-1,2,3,4-tetrahydronapht-6-yl)-2-hydroxy-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(phenylamino)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-chlorophenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-chlorophenyl)-2-hydroxy-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluorophenyl)-2-oxo-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;and9-[2-(3-fluorophenyl)-2-hydroxy-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;or a pharmaceutically acceptable salt thereof.
 5. The method accordingto claim 1, wherein said compound of formula I is selected from thegroup consisting of:1-[2-(1H-Indol-3-yl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(phenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(phenyl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(2-methylphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(2-methoxyphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-(4-phenylbutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(2-chlorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(2,5-dimethoxyphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(4-methylphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(3-methoxyphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(3,4,5-trimethoxyphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(4-fluorophenoxy)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(4-chlorophenoxy)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(2,4-dichlorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(phenylthio)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-(3-phenylpropanoyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(4-fluorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(3,4-difluorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-(2-cyclohexylethyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-(3,3-dimethylbutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-(2-phenyl-2-oxo-ethyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,(S)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-(4,4,4-trifluoro-but-2-en-1-yl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(4-trifluoromethylphenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,(R)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(2-fluorophenyl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(2,5-dimethoxy-phenyl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(phenylsulfonyl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-(4,4,4-trifluorobutyl)-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[3-(pyridin-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(2-methoxy)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(4-chloro-phenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(napht-2-yl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(3-methoxy-4,5-methylendioxy-phenyl)-2-oxo-1-methyl-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(4-phenyl-phenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(4-methylphenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapht-2-yl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,1-[2-(4-fluorophenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,and1-[2-(3-methoxyphenyl)-2-oxo-ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one;or a pharmaceutically acceptable salt thereof.